Fenofibrate pharmaceutical composition having high bioavailability

ABSTRACT

The invention provides fenofibrate tablets comprising granulates, wherein the granulates can comprise carrier particles, micronized fenofibrate, and at least one hydrophilic polymer.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.10/126,875 filed Apr. 22, 2002; which is a continuation of U.S.application Ser. No. 10/078,500 filed Feb. 21, 2002; which is acontinuation of U.S. application Ser. No. 09/899,026 filed Jul. 6, 2001;which is a continuation of U.S. application Ser. No. 09/572,330 filedMay 18, 2000, issued as U.S. Pat. No. 6,277,405; which is a continuationof U.S. application Ser. No. 09/005,128 filed Jan. 9, 1998, issued asU.S. Pat. No. 6,074,670; which claims priority to French Application No.97 00 479 filed Jan. 17, 1997.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to a novel pharmaceuticalcomposition having high bioavailability through improved dissolution,and a method for preparing it. The invention more particularly relatesto a pharmaceutical composition for administration by oral route,containing an active ingredient of poor aqueous solubility.

[0003] Numerous active ingredients suffer from the disadvantage of beingpoorly soluble in an aqueous medium, thus having an insufficientdissolution profile and, consequently, poor bioavailability within theorganism, following oral administration. The therapeutic dose requiredto be administered must thus be increased in order to obviate thisdisadvantage. This particularly applies to numerous hypolipemiant activeingredients, such as those belonging to the fibrate family.

[0004] Fenofibrate is a well-known hypolipemiant from the family offibrates, which is commercially available in various doses (100 and 300mg for example Secalip®) but in a form leading to poor bioavailabilityof the active ingredient. Indeed, due to it poor hydrosolubility,fenofibrate is poorly absorbed in the digestive tract and consequentlyits bioavailability is incomplete, irregular and often varies from oneperson to another.

[0005] To improve the dissolution profile of fenofibrate and itsbioavailability, thereby reducing the dose requiring to be administered,it would be useful to increase its dissolution so that it could attain alevel close to 100%.

[0006] Moreover, for patient comfort, it is advantageous to seek adosage form that only requires the medicament to be taken once dailywhile giving the same effect as one administered several times daily.

[0007] EP-A-0330532 discloses a method for improving bioavailability offenofibrate. This patent describes the effect of co-micronizingfenofibrate with a surfactant, for example sodium laurylsulfate in orderto improve fenofibrate solubility and thereby increase itsbioavailability. This patent teaches that co-micronizing fenofibratewith a solid surfactant improves fenofibrate bioavailability to a muchgreater extent than the improvement that would be obtained either byadding a surfactant, or through solely micronizing the fenofibrate, or,yet again, through intimately mixing the fenofibrate and surfactant,micronized separately. The dissolution method employed is theconventional rotating blade technique (European Pharmacopoeia): productdissolution kinetics are measured in a fixed volume of the dissolutionmedium, agitated by means of a standardized device; a test was alsocarried out with an alternative technique to the European Pharmacopoeia,using the continuous-flow cell method.

[0008] The process of EP-A-0330532 leads to a new dosage form in whichthe active ingredient, co-micronized with a solid surfactant, hasimproved fenofibrate dissolution, and thus increased bioavailability,which makes it possible, for a given level of effectiveness, to decreasethe daily dose of the medicament: respective 67 mg and 200 mg instead of100 mg and 300 mg.

[0009] However, the preparation method in that patent is not completelysatisfactory inasmuch as it does not lead to complete bioavailability ofthe active ingredient, and suffers from several disadvantages. Thetechnique of co-micronizing fenofibrate with a solid surfactant does, itis true, improve dissolution of the active ingredient, but thisdissolution remains, however, incomplete.

[0010] There is thus a need to improve fenofibrate bioavailability inorder to attain, over very short periods of time, a level close to 100%(or, in any case, better than the following limits: 10% in 5 minutes,20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes in a mediumconsisting of 1200 ml water to which 2% Polysorbate 80 is added, or of1000 ml of water to which 0.025M sodium lauryl sulfate sodium is added,with a blade rotation speed of 75 rpm), and this even when dissolutionmedia having a low surfactant content are used.

[0011] Applicant has found that, surprisingly, it is possible to resolvethis problem by a new method for preparing a pharmaceutical compositionby spraying a suspension of the active ingredient onto an inerthydrosoluble carrier. The present invention also relates topharmaceutical compositions thus prepared.

[0012] The use is already known of a polymer, such aspolyvinylpyrrolidone for producing tablets, in concentrations of theorder of 0.5 to 5% by weight, at a maximum 10% by weight. In this case,the polyvinylpyrrolidone is used as a binder. Similarly, the use of apolymer such as hydroxymethylpropylmethyl cellulose as a granulationbinder is known. Thus, European patent application 0,519,144 disclosespellets of a poorly soluble substance, omeprazole, obtained by sprayinga dispersion or suspension of the active ingredient in a solutioncontaining said polymer onto inert pellets in a fluidized-bedgranulator. However, here again, the polymer (HPMC and HPC) is only usedas a granulation binder, in an amount of about 50% by weight, based onthe weight of the active ingredient, which, bearing in mind the presenceof the inert pellets of a large size (about 700 μm) and the overallfinal weight leads to final active ingredient and polymer contents whichare very low, of the order of barely a few percent based on the weightof the final covered pellet. Finally, it will be noted that the size ofthe inert pellets in this documents is fairly large, which, in the caseof fenofibrate, would lead to a final formulation having a volume whichis much too large for ready oral administration.

[0013] The use of polymer, such as polyvinylpyrrolidone formanufacturing “solid dispersions” is also known, obtained in general byco-precipitation, co-fusion or liquid-phase mixing followed by drying.What we have here is fixation of the active ingredient in isolatedmicroparticles on the polyvinylpyrrolidone, which avoids problems ofpoor wetting of the solid and re-agglomeration of the particles. Thearticle “Stable Solid Dispersion System Against Humidity” by Kuchiki etal., Yakuzaigaku, 44 No. 1, 31-37 (1984) describes such a technique forpreparing solid dispersions using polyvinylpyrrolidone. The amounts ofPVP here are very high, and the ratio between the active ingredient andPVP are comprised between 1/1 and 1/20. In the case however there is noinert carrier.

[0014] WO-A-96 01621 further discloses a sustained release composition,comprising an inert core (silica in all examples) coated with a layerwhich contains the active ingredient in admixture with a hydrophilicpolymer, the weight ratio active ingredient/polymer being comprisedbetween 10/1 and 1/2 and the weight ratio active ingredient/inert corebeing comprised between 5/1 and 1/2, with an outer layer to impart thesustained release property. These compositions can be compressed. Thehydrophilic polymer can be polyvinylpyrrolidone. This document alsodiscloses a process for preparing said composition; for example in afluidized-bed granulator one will spray a dispersion of activeingredient in a polymer solution onto the inert cores. This documentsolely relates to sustained release compositions, the technical problemto be solved being the compression, without damages, of the outer layerimparting the sustained release property.

[0015] Nevertheless, nothing in the state of the art teaches nor suggestthe present invention.

SUMMARY OF THE INVENTION

[0016] Thus, the present invention provides an immediate-releasefenofibrate composition comprising:

[0017] (a) an inert hydrosoluble carrier covered with at least one layercontaining a fenofibrate active ingredient in a micronized form having asize less than 20 μm, a hydrophilic polymer and, optionally, asurfactant; said hydrophilic polymer making up at least 20% by weight of(a); and

[0018] (b) optionally one or several outer phase(s) or layer(s).

[0019] In one embodiment, a surfactant is present with the activeingredient and the hydrophilic polymer.

[0020] The invention also provides a composition comprising fenofibratehaving a dissolution of at least 10% in 5 minutes, 20% in 10 minutes,50% in 20 minutes and 75% in 30 minutes, as measured using the rotatingblade method at 75 rpm according to the European Pharmacopoeia, in adissolution medium constituted by water with 2% by weight polysorbate 80or in a dissolution medium constituted by water with 0.025M sodiumlauryl sulfate.

[0021] A method for preparing a pharmaceutical composition is alsoprovided, comprising the steps of:

[0022] (a) preparing a fenofibrate suspension in micronized form with aparticle size below 20 μm, in a solution of hydrophilic polymer and,optionally surfactant;

[0023] (b) applying the suspension from step (a) to an inerthydrosoluble carrier;

[0024] (c) optionally, coating granules thus obtained with one orseveral phase(s) or layer(s).

[0025] Step (b) is preferably carried out in a fluidized-bed granulator.

[0026] The method can comprise a step in which products obtained fromstep (b) or (c) are compressed, with or without additional excipients.

[0027] The invention also provides a suspension of fenofibrate inmicronized form having a size less than 10 μm, in a solution ofhydrophilic polymer and, optionally, surfactant.

[0028] The invention will be described in more detail in the descriptionwhich follows, with reference to the attached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029]FIG. 1 is a graph of a comparative study of the dissolutionprofile of a composition according to the invention, compared to that ofLipanthyl® 200M;

[0030]FIG. 2 is a graph illustrating a comparative study of thedissolution profile of a composition according to the invention and thatof pharmaceutical products commercially available on the German market.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0031] The expression “in micronized form” in this invention means asubstance in a particulate form, the dimensions of the particles beingless than or equal to about 20 μm.

[0032] Advantageously, this dimension is less than or equal to 10 μm.

[0033] In the framework of this invention, the expression “inerthydrosoluble carrier” means any excipient, generally hydrophilic,pharmaceutically inert, crystalline or amorphous, in a particulate form,not leading to a chemical reaction under the operating conditionsemployed, and which is soluble in an aqueous medium, notably in agastric acid medium. Examples of such excipients are derivatives ofsugars, such as lactose, saccharose, hydrolyzed starch (malto-dextrine),etc. Mixture are also suitable. The individual particle size of theinert hydrosoluble carrier can be, for example, between 50 and 500micron.

[0034] The expression “hydrophilic polymer” in the invention should betaken to mean any high molecular weight substance (greater, for example,than 300) having sufficient affinity towards water to dissolve thereinand form a gel. Examples of such polymers are polyvinylpyrrolidone,poly(vinyl alcohol), hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, etc. Polymer blends are alsosuitable.

[0035] The preferred hydrophylic polymer is polyvinylpyrrolidone (PVP).The PVP used in this invention has, for example, a molecular weightcomprised between 10,000 and 100,000, preferably for example between20,000 and 55,000.

[0036] The term “surfactant” is used in its conventional sense in thisinvention. Any surfactant is suitable, whether it be amphoteric,non-ionic, cationic or anionic. Examples of such surfactants are: sodiumlauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate oranother ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate(DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol,polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides,poloxamer®, etc. Mixtures of surfactants are also suitable.

[0037] The preferred surfactant is sodium laurylsulfate, which can beco-micronized with fenofibrate.

[0038] The compositions according to the invention can additionallycontain any excipient conventionally used in the pharmaceutical andchemical fields which is compatible with the active ingredient, such asbinders, fillers, pigments, disintegrating agents, lubricants, wettingagents, buffers, etc. As examples, excipients able to be used in thisinvention we can cite: microcrystalline cellulose, lactose, starch,colloidal silica, talc, glycerol esters, sodium stearyl fumarate,titanium dioxide, magnesium stearate, stearic acid, cross-linkedpolyvinyl pyrrolidone (AC DI SOL®), carboxymethyl starch (Explotab®,Primojel®), hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, etc.

[0039] Here, the expression “outer phase or layer” should be taken tomean any coating on the element (a) with the active ingredient (forminga “core”). Indeed, it can be useful to have available one or severalphase(s) or layer(s) on top of the coated core. The invention thuscovers a single core with one layer, but also several cores in a phase,as is the case of tablets which are formed from “cores” mixed with aphase.

[0040] This outer layer comprises conventional excipients.

[0041] It is also possible to provide a layer comprising additives, forthe manufacture of tablets. In this embodiment, the outer layercomprises a disintegration agent and, for example, a lubricant; the thuscovered and mixed granules can then be readily compressed and easilydisintegrate in water.

[0042] The compositions according to the invention comprise, in general,based on the total composition weight excluding the outer phase orlayer, an inert hydrosoluble carrier making up from 10 to 80% by weight,preferably 20 to 50% by weight, the fenofibrate representing from 5 to50% by weight, preferably from 20 to 45% by weight, the hydrophilicpolymer representing from 20 to 60% by weight, preferably 25 to 45% byweight, the surfactant making up from 0 to 10% by weight, preferably 0.1to 3% by weight.

[0043] The outer layer or phase if present, can make up to 80% by weightof the total weight, preferably up to 50% by weight.

[0044] The hydrophilic polymer represents preferably more than 25% byweight, based on the weight of (a).

[0045] The weight ratio of fenofibrate/hydrophilic polymer can forexample be comprised between 1/10 and 4/1, preferably, for example,between 1/2 and 2/1.

[0046] When a surfactant is employed, the weight ratiosurfactant/hydrophilic polymer can be comprised for example between1/500 and 1/10, preferably, for example, between 1/100 and 5/100.

[0047] In one embodiment, the composition according to the inventiontakes the form of tablets.

[0048] This tablet preferably results from the compression of elements(a) (under the form of granules) together with an outer phase.

[0049] In another embodiment, the composition of the invention takes theform of granules enclosed inside a capsule, for example in gelatin, orinside a bag.

[0050] The compositions of the invention are particularly suitable foradministering active ingredients by oral route.

[0051] The composition according to the invention is prepared by a novelprocess comprising spraying a suspension of the active ingredient in amicronized form in a solution of a hydrophilic polymer and, optionally,a surfactant, onto the inert core.

[0052] When a surfactant is present, the active ingredient can beco-micronized with the surfactant. One will then use with advantage theteachings of EP-A-0330532.

[0053] The method according to the invention consists in using thefluidized bed granulation principle, but with specific startingmaterials, in order to arrive at an improved dissolution profile andthus, at elevated bioavailability. In particular, the invention employsa suspension of the micronized active ingredient in a solution of ahydrophylic polymer and, optionally, a surfactant.

[0054] The fluidized-bed granulation technique is widely used in thepharmaceutical industry for preparing capsules or tablets.Conventionally, according to the prior art, a powder or a mixture ofpowders (active ingredient+excipients) is put into suspension in thefluidized bed in a granulator, and a solution containing a binder and,optionally, a surfactant, is sprayed onto this bed to form granules. Thefluidized-bed granulation technique is well known to those skilled inthe art and reference should be made to standard works such as forexample “Die Tablette”, by Ritschel, Ed. Cantor Aulendorf, pages211-212.

[0055] The invention, as has been indicated, comprises spraying asuspension of an active ingredient micronized with a hydrophilic polymeronto an inert carrier. Following granulation, the granulate formedconsists of crystals of, for example, lactose, which are isolated (orpossibly agglomerated together by the spray solution) and particles ofactive ingredient and PVP adhering to the crystal surface. The granulecould similarly be constituted of coated crystals which areagglomerated, or even of such an agglomerate having received a coating.

[0056] The compositions according to the invention can also be preparedby other methods, for example by spraying a solution of the micronizedactive ingredient onto the hydrosoluble inert carrier.

[0057] The granulates thus obtained can, if desired, be provided with anouter coating or compressed into tablets, or form agglomerates.

[0058] The outer layer or layer is/are applied using conventionalcoating techniques such as coating in a pan or fluidized bed coater.

[0059] When the granulate obtained (whether subsequently coated or not)is compressed to form tablets, this step can be implemented using anyconventional technique which is suitable, for example using analternating or rotating compressing equipment.

[0060] The significant starting product is the suspension of the activeingredient. This suspension is prepared by putting the micronized activeingredient into suspension in a solution comprising the hydrophylicpolymer and, optionally, a surfactant, in solution in a solvent. If asurfactant is employed, it is put into solution in the solvent(beaker+magnetic or vane stirrer). Next, the hydrophylic polymer (PVP)is dispersed, while stirring, in the solution previously obtained.Depending on polymer solubility, this either dissolves in the solutionor forms a gel or a suspension having varying degrees of thickness.While still stirring, the micronized active ingredient is dispersed inthe form of a fine shower into the above solution or suspension, to forma homogeneous suspension. The order of these steps can be reversed. Thesolvent employed can be aqueous or organic (for example ethanol). Forexample demineralized water can be used.

[0061] The active ingredient concentration in the suspension is from 1to 40% by weight, preferably from 10 to 25%.

[0062] The hydrophylic polymer concentration in the suspension is from 5to 40% by weight, preferably 10 to 25%.

[0063] The surfactant concentration in the suspension is from 0 to 10%by weight, preferably below 5%.

[0064] The invention also covers this novel suspension.

[0065] Without wishing to be tied down to a specific theory, applicantbelieves that this novel method, through the use of a micronized activeingredient suspension in a hydrophilic polymer solution, enabled a novelcomposition to be obtained in which the active ingredient is in anon-re-agglomerated form.

[0066] The following examples illustrate the invention without limitingit.

EXAMPLE 1

[0067] Preparation of a pharmaceutical composition of fenofibrateaccording to the invention.

[0068] A composition containing, as the element a), micronizedfenofibrate, Plasdone®, Capsulac® and sodium lauryl sulfate wasprepared.

[0069] The micronized fenofibrate had a particle size of about 5 μm, asmeasured using a Coulter counter.

[0070] The Plasdone K25® corresponds to a polyvinylpyrrolidone PVP ISPand the Capsulac 60® corresponds to a coarse crystal lactose monohydrate(Meggle) (particle size between 100 and 400 μm).

[0071] The sodium laurylsulfate (7 g) is dissolved in water(demineralized water, 1750 g) and the micronized fenofibrate (350 g) isput into suspension in the mixture obtained (for example using a helixstirrer at 300 rpm for 10 minutes, then using an Ultra Turrax agitatorat 10,000 rpm, for 10 minutes). Following this, the PVP (350 g) is addedwhile still agitating, stirring (helix stirrer) being continued untilthe latter had dissolved (30 minutes). It is all passed through a sieve(350 μm) to eliminate possible agglomerates.

[0072] Separately, the lactose (400 g) is put into suspension in afluidized air bed granulator (of the Glatt® GPCGI—Top Spray type orequivalent) and heated to a temperature of 40° C.

[0073] The fenofibrate suspension is sprayed onto the lactose. This stepis carried out under the following conditions: spraying pressure: 2.1bar, air throughput 70 m³/h, air inlet temperature: 45° C.; air outlettemperature: 33° C.; product temperature 34° C.; duration of spraying: 3h.

[0074] The granulate thus obtained can be put inside capsules ortransformed into tablets. Any suitable conventional technique forpreparing such dosage forms can be used.

[0075] For transformation to tablet form, one will mix 191 g of thegranulate obtained (using for example a mixer-grinder type mixingapparatus, a planetary mixer or turn-over mixer), with the outer phasehaving the following composition:

[0076] 56 g Polyplasdone XL® (cross-linked polyvinylpyrrolidone ISP, asdescribed in the USA Pharmacopoeia “USP—NF” under the name ofcrospovidone, mean molecular weight>1,000,000);

[0077] 88 g Avicel® PH200 (microcrystalline cellulose);

[0078] 3.5 g sodium stearyl fumarate (Mendell, U. S. A.); and

[0079] 2 g Aerosil® 200 (colloidal silica).

[0080] The cross-linked polyvinylpyrrolidone, the microcrystallinecellulose, the sodium stearyl fumarate and the colloidal silica arerespectively, disintegration agents, binders, lubricating and flowenhancing agents.

[0081] The tablet can be obtained on an alternating compression machine(for example Korsch EKO) or a rotary machine (for example Fette Perfecta2).

[0082] One thus obtains tablets having the following composition,expressed in mg: element (a): micronized fenofibrate 100.0 PVP 100.0Lactose 114.3 sodium laurylsulfat 2.0 outer phase (or layer):cross-linked PVP 92.7 microcrystalline cellulos 145.7 sodium stearylfumarate 5.8 colloidal silica 3.3

EXAMPLE 2

[0083] Dissolution of a composition according to the invention and acomposition according to the prior art.

[0084] a) dissolution medium and procedure for measuring dissolution.

[0085] A dissolution medium which is discriminating, in other words onein which two products having very different dissolution profiles ingastric juices will have very different dissolution curves is lookedfor.

[0086] For this, an aqueous medium containing a surfactant, this beingPolysorbate 80 (polyoxyethylene sorbitane mono-oleate) is used. Thissurfactant is readily available from various suppliers, is the object ofa monograph in the Pharmacopoeias, and is thus easy to implement (beingalso a water-soluble liquid product). Other surfactants can also beused.

[0087] The rotating blade method (European Pharmacopoeia) is used underthe following conditions: volume of medium: 1200 ml; medium temperature:37° C.; blade rotation speed: 75 rpm; samples taken: every 2.5 minutes.Determination of the amount dissolved is carried out byspectrophotometry. Test are repeated 6 times over.

[0088] b) Results

[0089] The composition according to the invention consisted of twotablets containing about 100 mg fenofibrate prepared according toExample 1.

[0090] The prior art composition was Lipanthyl® 200M from LaboratoiresFournier, containing 200 mg fenofibrate (corresponding to capsules of200 mg fenofibrate, co-micronized with sodium laurylsulfate, andcontaining lactose, pre-gelatinized starch, cross-linkedpolyvinylpyrrolidone and magnesium stearate, in line with the teachingsof EP-A-0330532).

[0091] The results obtained are shown graphically in FIG. 1, on whichthe percentage of dissolution is shown, the observed standard deviationbeing indicated between brackets.

[0092] These results clearly show that the compositions according to theinvention have a dissolution profile which is distinctly better thanthat of the prior art compositions.

[0093] These results also clearly show that with the compositions of theinvention, the standard deviation observed is distinctly lower than isthe case with prior art compositions.

EXAMPLE 3

[0094] Study of bioavailability of compositions according to theinvention and prior art compositions.

[0095] A test of bioavailability on healthy volunteers was carried out.

[0096] The following compositions were tested:

[0097] composition according to the invention: capsules containinggranules prepared according to example 1, containing 200 mg fenofibrate.

[0098] first composition according to the prior art: Lipanthyl® 200Mfrom Laboratoires Fournier, containing 200 mg fenofibrate, identical tothat in the previous example.

[0099] second prior art composition: Secalip® in capsule form (300 mgfenofibrate in the form of three 100 mg capsules).

[0100] The study was carried out on 6 healthy volunteers receiving asingle dose of fenofibrate, with a minimum 6-day rest period betweenadministrations. The samples for pharmaco-kinetic analysis werecollected after each administration at the following times: 0.5 h; 1 h;2 h; 3 h; 4 h; 5 h; 6 h; 8 h; 10 h; 12 h; 24 h; 36 h; 48 h; 72 h; and 96hours following administration of the medicament. Fenofibric acidcontent in plasma was measured for each sample.

[0101] The results obtained are given in table 1 below. TABLE 1 doseCmax AUC 0-t AUC 0-∞ Product (mg) (μg/ml) tmax (h) t ½ (h) (μg.h/ml)(μg.h/ml) Invention 200 5.4 6 23 148  162  Secalip ® 100 3 × 100 1.1 2539 53 56 Lipanthyl ® 200M 200 1.6 8.3 41 71 92

[0102] The results clearly show that the compositions of the presentinvention have a dissolution profile that is an improvement overcompositions of the prior art, leading to a considerably enhancedbioavailability of the active ingredient compared to that obtained withcompositions of the prior art.

EXAMPLE 4

[0103] Comparison of the dissolution profile of compositions accordingto the invention and that of products currently on the German market.

[0104] On the German market, immediate or sustained-release fenofibrateformulations exist. Like in France, the 100 mg and 300 mg (conventional)forms coexist with 67 and 200 mg forms (having enhanced bioavailability,according to the teaching of EP-A-0330532). These products are asfollows:

[0105] Fenofibrate—ratiopharm; Ratiopharm—Ulm;

[0106] Capsules;

[0107] Composition: 100 mg fenofibrate;

[0108] Excipients: lactose, corn starch, magnesium stearate, E 171colorant, gelatine.

[0109] Durafenat; Durachemie—Wolfratshausen Capsules;

[0110] Composition: 100 mg fenofibrate;

[0111] Excipients: lactose, corn starch, magnesium stearate, E 171colorant, gelatine.

[0112] Normalip pro; Knoll—Ludwigshafen;

[0113] Capsules;

[0114] Composition: 200 mg Fenofibrate;

[0115] Excipients: Crospovidone, gelatine, monohydrate lactose,magnesium stearate, corn starch, sodium laurylsulfate, E 132 and E 171colorants.

[0116] A comparison was made between:

[0117] the tablet of the invention as prepared using example 1 (2×100mg)

[0118] Normalip pro® (200 mg);

[0119] Lipanthyl® 200M (200 mg) (according to the preceding example);

[0120] Fenofibrate by Ratiopharm® (2×100 mg);

[0121] Durafenat® (2×100 mg)

[0122] The tests were implemented under the same conditions as in theprevious examples. FIG. 2 summarizes the results.

[0123] These results clearly show that the compositions of the inventionhave a distinctly improved dissolution compared to prior artcompositions.

[0124] Obviously, the present invention is not limited to theembodiments described but may be subject to numerous variations readilyaccessible to those skilled in the art.

What is claimed is:
 1. A fenofibrate tablet comprising granulates,wherein the granulates comprise carrier particles and one or more layerscomprising micronized fenofibrate and at least one hydrophilic polymer,wherein the one or more layers are on the carrier particles.
 2. Thetablet of claim 1, wherein the carrier particles have a particle sizebetween 50 and 500 microns.
 3. The tablet of claim 1, wherein thecarrier particles have a particle size between 100 and 400 microns. 4.The tablet of claim 1, wherein the carrier particles comprise lactose,saccharose, hydrozyled starch, or a mixture of two or more thereto. 5.The tablet of claim 1, wherein the granulates further comprise at leastone surfactant.
 6. The tablet of claim 5, wherein the surfactant issodium lauryl sulfate, monooleate polyoxyethylene sorbitane, monolauratepolyoxyethylene sorbitane, monopalmitate polyoxyethylene sorbitane,monostearate polyoxyethylene sorbitane, sodium dioctylsulfosuccinate,lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol,polyoxyethylene ricin oil, polyoxyethylene fatty acid glyceride, apoloxamer, or a mixture of two or more thereof.
 7. The tablet of claim5, wherein the surfactant is sodium lauryl sulfate.
 8. The tablet ofclaim 5, wherein the surfactant is present in an amount of 0.1 to 10% byweight.
 9. The tablet of claim 1, wherein the at least one hydrophilicpolymer is a mixture of hydrophilic polymers.
 10. The tablet of claim 1,wherein the hydrophilic polymer is polyvinylpyrrolidone, poly(vinylalcohol), hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, or a mixture of two or morethereof.
 11. The tablet of claim 1, wherein the hydrophilic polymer ispolyvinylpyrrolidone.
 12. The tablet of claim 1, wherein the compositionfurther comprises at least one pharmaceutical excipient.
 13. The tabletof claim 12, wherein the at least one pharmaceutical excipient is atleast one binder, at least one filler, at least one pigment, at leastone disintegrating agent, at least one lubricant, at least one wettingagent, at least one buffer, or a mixture of two or more thereof.
 14. Thetablet of claim 12, wherein the at least one pharmaceutical excipient isat least one disintegrating agent, at least one lubricant, or a mixturethereof.
 15. The tablet of claim 1, wherein the granulates furthercomprise at least one outer phase and/or layer.
 16. The tablet of claim15, wherein the at least one outer phase and/or layer comprises at leastone pharmaceutical excipient.
 17. The tablet of claim 16, wherein the atleast one pharmaceutical excipient is at least one binder, at least onefiller, at least one pigment, at least one disintegrating agent, atleast one lubricant, at least one wetting agent, at least one buffer, ora mixture of two or more thereof.
 18. The tablet of claim 16, whereinthe at least one pharmaceutical excipient is at least one disintegratingagent, at least one lubricant, or a mixture thereof.
 19. The tablet ofclaim 1, wherein two or more granulates are agglomerated together. 20.The tablet of claim 1, wherein the micronized fenofibrate have aparticle size less than or equal to 10 microns.
 21. The tablet of claim1, wherein the weight ratio of micronized fenofibrate to hydrophilicpolymer is between 1:10 and 4:1.
 22. The tablet of claim 1, wherein thecarrier particles present in an amount of 10 to 80% by weight.
 23. Thetablet of claim 1, wherein the carrier particles are present in anamount of 20 to 50% by weight.
 24. The tablet of claim 1, wherein themicronized fenofibrate is present in an amount of 5 to 50% by weight.25. The tablet of claim 1, wherein the hydrophilic polymer is present inan amount of 20 to 60% by weight.
 26. The tablet of claim 1, wherein thehydrophilic polymer is present in an amount of 25 to 45% by weight. 27.A fenofibrate tablet comprising granulates, wherein the granulatescomprise carrier particles, micronized fenofibrate, and at least onehydrophilic polymer; and wherein the tablet has a dissolution of atleast 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in30 minutes, as measured using the rotaing blade method at 75 rpmaccording to the European Pharmacopoeia, in a dissolution mediumconstituted by water with 2% by weight polysorbate 80 or a dissolutionmedium constituted by water with 0.025 M sodium lauryl sulfate.
 28. Thetablet of claim 27, wherein the carrier particles have a particle sizebetween 50 and 500 microns.
 29. The tablet of claim 27, wherein thecarrier particles have a particle size between 100 and 400 microns. 30.The tablet of claim 27, wherein the carrier particles comprise lactose,saccharose, hydrozyled starch, or a mixture of two or more thereto. 31.The tablet of claim 27, wherein the granulates further comprise at leastone surfactant.
 32. The tablet of claim 31, wherein the surfactant issodium lauryl sulfate, monooleate polyoxyethylene sorbitane, monolauratepolyoxyethylene sorbitane, monopalmitate polyoxyethylene sorbitane,monostearate polyoxyethylene sorbitane, sodium dioctylsulfosuccinate,lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol,polyoxyethylene ricin oil, polyoxyethylene fatty acid glyceride, apoloxamer, or a mixture of two or more thereof.
 33. The tablet of claim31, wherein the surfactant is sodium lauryl sulfate.
 34. The tablet ofclaim 31, wherein the surfactant is present in an amount of 0.1 to 10%by weight.
 35. The tablet of claim 27, wherein the hydrophilic polymeris a mixture of two or more hydrophilic polymers.
 36. The tablet ofclaim 27, wherein the hydrophilic polymer is polyvinylpyrrolidone,poly(vinyl alcohol), hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, or a mixture of two or morethereof.
 37. The tablet of claim 27, wherein the hydrophilic polymer ispolyvinylpyrrolidone.
 38. The tablet of claim 27, wherein thecomposition further comprises at least one pharmaceutical excipient. 39.The tablet of claim 38, wherein the at least one pharmaceuticalexcipient is at least one binder, at least one filler, at least onepigment, at least one disintegrating agent, at least one lubricant, atleast one wetting agent, at least one buffer, or a mixture of two ormore thereof.
 40. The tablet of claim 39, wherein the at least onepharmaceutical excipient is at least one disintegrating agent, at leastone lubricant, or a mixture thereof.
 41. The tablet of claim 27, whereinthe granulates further comprise at least one outer phase and/or layer.42. The tablet of claim 41, wherein the at least one outer phase and/orlayer comprises at least one pharmaceutical excipient.
 43. The tablet ofclaim 42, wherein the at least one pharmaceutical excipient is at leastone binder, at least one filler, at least one pigment, at least onedisintegrating agent, at least one lubricant, at least one wettingagent, at least one buffer, or a mixture of two or more thereof.
 44. Thetablet of claim 42, wherein the at least one pharmaceutical excipient isat least one disintegrating agent, at least one lubricant, or a mixturethereof.
 45. The tablet of claim 27, wherein two or more granulates areagglomerated together.
 46. The tablet of claim 27, wherein themicronized fenofibrate have a particle size less than or equal to 10microns.
 47. The tablet of claim 27, wherein the weight ratio ofmicronized fenofibrate to hydrophilic polymer is between 1:10 and 4:1.48. The tablet of claim 27, wherein the carrier particles present in anamount of 10 to 80% by weight.
 49. The tablet of claim 27, wherein thecarrier particles are present in an amount of 20 to 50% by weight. 50.The tablet of claim 27, wherein the micronized fenofibrate is present inan amount of 5 to 50% by weight.
 51. The tablet of claim 27, wherein thehydrophilic polymer is present in an amount of 20 to 60% by weight. 52.The tablet of claim 27, wherein the hydrophilic polymer is present in anamount of 25 to 45% by weight.
 53. A fenofibrate tablet comprisinggranulates, wherein the granulates comprise carrier particles, at leastone hydrophilic polymer and micronized fenofibrate having a particlesize below 20 microns; and wherein the at least one hydrophilic polymerand micronized fenofibrate particles are adjacent to the surface of thecarrier particles.
 54. The tablet of claim 53, wherein the weight ratioof micronized fenofibrate to hydrophilic polymer is between 1:10 and4:1.
 55. The tablet of claim 53, wherein the carrier particles have aparticle size between 50 and 500 microns.
 56. The tablet of claim 53,wherein the carrier particles have a particle size between 100 and 400microns.
 57. The tablet of claim 53, wherein the carrier particlescomprise lactose, saccharose, hydrozyled starch, or a mixture of two ormore thereto.
 58. The tablet of claim 53, wherein the granulates furthercomprise at least one surfactant.
 59. The tablet of claim 58, whereinthe surfactant is sodium lauryl sulfate, monooleate polyoxyethylenesorbitane, monolaurate polyoxyethylene sorbitane, monopalmitatepolyoxyethylene sorbitane, monostearate polyoxyethylene sorbitane,sodium dioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylicalcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fattyacid glyceride, a poloxamer, or a mixture of two or more thereof. 60.The tablet of claim 58, wherein the surfactant is sodium lauryl sulfate.61. The tablet of claim 58, wherein the surfactant is present in anamount of 0.1 to 10% by weight.
 62. The tablet of claim 53, wherein theat least one hydrophilic polymer is a mixture of hydrophilic polymers.63. The tablet of claim 53, wherein the hydrophilic polymer ispolyvinylpyrrolidone, poly(vinyl alcohol), hydroxypropylcellulose,hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, or amixture of two or more thereof.
 64. The tablet of claim 53, wherein thehydrophilic polymer is polyvinylpyrrolidone.
 65. The tablet of claim 53,wherein the composition further comprises at least one pharmaceuticalexcipient.
 66. The tablet of claim 65, wherein the at least onepharmaceutical excipient is at least one binder, at least one filler, atleast one pigment, at least one disintegrating agent, at least onelubricant, at least one wetting agent, at least one buffer, or a mixtureof two or more thereof.
 67. The tablet of claim 65, wherein the at leastone pharmaceutical excipient is at least one disintegrating agent, atleast one lubricant, or a mixture thereof.
 68. The tablet of claim 53,wherein the granulates further comprise at least one outer phase and/orlayer.
 69. The tablet of claim 68, wherein the at least one outer phaseand/or layer comprises at least one pharmaceutical excipient.
 70. Thetablet of claim 69, wherein the at least one pharmaceutical excipient isat least one binder, at least one filler, at least one pigment, at leastone disintegrating agent, at least one lubricant, at least one wettingagent, at least one buffer, or a mixture of two or more thereof.
 71. Thetablet of claim 69, wherein the at least one pharmaceutical excipient isat least one disintegrating agent, at least one lubricant, or a mixturethereof.
 72. The tablet of claim 53, wherein two or more granulates areagglomerated together.
 73. The tablet of claim 53, wherein themicronized fenofibrate have a particle size less than or equal to 10microns.
 74. The tablet of claim 53, wherein the carrier particlespresent in an amount of 10 to 80% by weight.
 75. The tablet of claim 53,wherein the carrier particles are present in an amount of 20 to 50% byweight.
 76. The tablet of claim 53, wherein the micronized fenofibrateis present in an amount of 5 to 50% by weight.
 77. The tablet of claim53, wherein the hydrophilic polymer is present in an amount of 20 to 60%by weight.
 78. The tablet of claim 53, wherein the hydrophilic polymeris present in an amount of 25 to 45% by weight.
 79. A fenofibrate tabletcomprising granulates, wherein the granulates comprise carrier particleshaving a particle size between 50 and 500 microns, at least onehydrophilic polymer, and micronized fenofibrate having a particle sizebelow 20 microns; and wherein the granulates comprise at least one outerphase and/or layer which comprises at least one pharmaceuticalexcipient.
 80. The tablet of claim 79, wherein the weight ratio ofmicronized fenofibrate to hydrophilic polymer is between 1:10 and 4:1.81. The tablet of claim 79, wherein the carrier particles have aparticle size between 100 and 400 microns.
 82. The tablet of claim 79,wherein the carrier particles comprise lactose, saccharose, hydrozyledstarch, or a mixture of two or more thereto.
 83. The tablet of claim 79,wherein the granulates further comprise at least one surfactant.
 84. Thetablet of claim 83, wherein the surfactant is sodium lauryl sulfate,monooleate polyoxyethylene sorbitane, monolaurate polyoxyethylenesorbitane, monopalmitate polyoxyethylene sorbitane, monostearatepolyoxyethylene sorbitane, sodium dioctylsulfosuccinate, lecithin,stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylenericin oil, polyoxyethylene fatty acid glyceride, a poloxamer, or amixture of two or more thereof.
 85. The tablet of claim 83, wherein thesurfactant is sodium lauryl sulfate.
 86. The tablet of claim 83, whereinthe surfactant is present in an amount of 0.1 to 10% by weight.
 87. Thetablet of claim 79, wherein the at least one hydrophilic polymer is amixture of hydrophilic polymers.
 88. The tablet of claim 79, wherein thehydrophilic polymer is polyvinylpyrrolidone, poly(vinyl alcohol),hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, or a mixture of two or morethereof.
 89. The tablet of claim 79, wherein the hydrophilic polymer ispolyvinylpyrrolidone.
 90. The tablet of claim 79, wherein thecomposition further comprises at least one pharmaceutical excipient. 91.The tablet of claim 90, wherein the at least one pharmaceuticalexcipient is at least one binder, at least one filler, at least onepigment, at least one disintegrating agent, at least one lubricant, atleast one wetting agent, at least one buffer, or a mixture of two ormore thereof.
 92. The tablet of claim 90, wherein the at least onepharmaceutical excipient is at least one disintegrating agent, at leastone lubricant, or a mixture thereof.
 93. The tablet of claim 79, whereinthe at least one pharmaceutical excipient is at least one binder, atleast one filler, at least one pigment, at least one disintegratingagent, at least one lubricant, at least one wetting agent, at least onebuffer, or a mixture of two or more thereof.
 94. The tablet of claim 79,wherein the at least one pharmaceutical excipient is at least onedisintegrating agent, at least one lubricant, or a mixture thereof. 95.The tablet of claim 79, wherein two or more granulates are agglomeratedtogether.
 96. The tablet of claim 79, wherein the micronized fenofibratehave a particle size less than or equal to 10 microns.
 97. The tablet ofclaim 79, wherein the carrier particles present in an amount of 10 to80% by weight.
 98. The tablet of claim 79, wherein the carrier particlesare present in an amount of 20 to 50% by weight.
 99. The tablet of claim79, wherein the micronized fenofibrate is present in an amount of 5 to50% by weight.
 100. The tablet of claim 79, wherein the hydrophilicpolymer is present in an amount of 20 to 60% by weight.
 101. The tabletof claim 79, wherein the hydrophilic polymer is present in an amount of25 to 45% by weight.
 102. The tablet of claim 79, wherein the tablet hasa dissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20minutes and 75% in 30 minutes, as measured using the rotaing blademethod at 75 rpm according to the European Pharmacopoeia, in adissolution medium constituted by water with 2% by weight polysorbate 80or a dissolution medium constituted by water with 0.025 M sodium laurylsulfate.